利妥昔单抗治疗活动增殖性狼疮性肾炎的有效性和安全性（LUNAR研究）
赵金霞
摘要 背景：许多狼疮性肾炎患者在治疗1年后仅为部分缓解，提示需要更有效的治疗方法。在本项随机双盲安慰剂对照的3期临床研究中，主要评价利妥昔单抗联合吗替麦考酚酯（MMF）和激素治疗狼疮肾炎的有效性和安全性。
方法：144例III 或IV型狼疮性肾炎患者以1:1随机分为利妥昔单抗组（1,15,168和182天分别给予利妥昔单抗1000mg）和安慰剂组。主要研究终点为52周时的治疗反应。
结果：利妥昔单抗组清除了71例患者（共72例）外周血的CD19+B细胞。完全和部分治疗反应的比例分别为安慰剂组33/77（45.8%）和利妥昔单抗治疗组的41/72（56.9%）(P=0.55)，两者的差异主要体现在部分治疗反应率。主要研究终点（利妥昔单抗组治疗反应率更佳）并未达到。在52周内，有8例安慰剂组患者需要接受环磷酰胺的补救治疗，而利妥昔单抗组无1例需要。利妥昔单抗组患者血清补体C3、C4和抗ds-DNA抗体水平较安慰剂组患者显著改善。两组患者中，抗ds-DNA抗体水平降低超过中位数值的与蛋白尿的改善密切相关。感染等严重不良反应的发生率两组相当。利妥昔单抗组中中性粒细胞减少、白细胞减少和低血压的发生率更高。
结论：尽管利妥昔单抗组患者治疗反应率更高且抗ds-DNA抗体和C3/C4水平改善更显著，治疗1年后的临床结果并未改善。利妥昔单抗与MMF和激素联合治疗并未带来新的或意外的安全性信号。
附原文：BACKGROUND: Many lupus nephritis (LN) patients show only partial renal responses after 1 year of treatment, indicating the need for a more effective therapeutic regimen. We evaluated the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase 3 trial in LN patients treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids. METHODS: Patients (n=144) with Class III or IV LN were randomized 1:1 to rituximab (1000 mg) or placebo on days 1, 15, 168, and 182. The primary endpoint was renal response status at Week 52. RESULTS: Rituximab depleted peripheral CD19+ B cells in 71/72 patients. Complete and partial renal responses were achieved in 33/72 (45.8%) placebo- and 41/72 (56.9%) rituximab-treated patients (P=0.55), the difference mostly accounted for by partial responses. The primary endpoint (superior response rate with rituximab) was not achieved. Eight placebo patients and no rituximab-treated patients required cyclophosphamide rescue therapy through Week 52. Statistically significant improvements in serum complement C3, C4, and anti-dsDNA antibody levels were observed with rituximab. In both treatment groups, a reduction in anti-dsDNA greater than the median reduction was associated with improvement in proteinuria. Rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group. CONCLUSIONS: Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.
引自:Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G; for the LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab (LUNAR) study. Arthritis Rheum. 2012 Jan 9. doi: 10.1002/art.34359. [Epub ahead of print]
